Benzomorphan derivatives

ABSTRACT

BENZOMORPHANES OF THE FORULA:   3-R,6-R1,8-(X-CO-A-O-),11-R&#34;-1,2,3,4,5,6-HEXAHYDRO-2,6-   METHANO-3-BENZAZOCINE   WHEREIN R IS METHYL, CYCLOPROPYLMETHYL OR CYCLOBUTYLMETHYL, R&#39;&#39; AND R&#34; ARE THE SAME OR DIFFERENT, AND ARE STRAIGHT OR BRANCHED CHAIN HYDROCARBONS OF 1 TO 5 CARBON ATOMS, X IS OH, OR&#34;&#34; OR   -N(-R4)-R5   WHEREIN R&#34;&#39;&#39; IS ASTRAIGHT OR BRANCHED CHAIN, SATURATED OR UNSATURTED HYDROCARBON OF 11 TO 11 CARBON ATOMS, R4 AND R5 ARE THE SAME OR DIFFERENT, AND ARE HYDROGEN, A STRAIGHT OR BRANCHED CHAIN, SAURATED HYDROCARON OF 1 TO 4 CARBON ATOMS, OR R4 AND R5 TOGETHER WITH THE NITROGEN ATOM FORM A5- OR 6-MEMBERED HETEROCYCLIC RING WHICH MAY HAVE OXYGEN AS A SECOND HETEROATOM, AND A IS A BIVALENT, STRAIGHT OR BRACHED CHAIN, SATURATED OR UNSATURATED HYDROCARBON OF 1 TO 10 CARBON ATOMS, SAID HYDROCARBON SUBSTITUTED BY 1 OR MORE PHENYL MOIETIES, OR SAID HYDROCARBON SUBSTITUTED BY 1 OR MORE ALKYL, ALKOXY, HALOGEN, NITRO OR ACYLAMINO SUBSTITUTED PHENYL MOIETIES, AND PHARMACEUTICALLY ACCEPTABLE NON-TOXIC SALTS THEREOF ARE PRODUCED BY REACTING A BENZOMORPHAN OF THE FORMULA:   8-HO,6-R&#39;&#39;,11-R&#34;,3-R-1,2,3,4,5,6-HEXAHYDRO-2,6-METHANO-   3-BENZAZOCINE   WHEREIN R&#39;&#39; AND R&#34; ARE AS ABOVE DEFINED, AND Y IS HYDROGEN, METHYL, CYCLOPROPYLMETHYL, CYCLOBUTYLMETHYL, OR THE MOIETY -CO-R6, WHEREIN R6 IS CYCLOPROPYL OR CYCLOBUTYL, IN THE PRESENCE OF AN ACIDBINDING AGENT, OR BY REACTING SAID BENZOMORPHAN IN THE FORM O A METAL OR AMMONIUM SALT WITH A REACTIVE ESTER OF A HYDROXY COMPOUND OFTHE FORMULA:   Z-A-OH   WHEREIN A IS AS ABOVE DEFINED, AND Z IS CO-X OR CN TO GIVE A COMPOUND OF THE FORMULA   8-(Z-A-O-),6-R&#39;&#39;,11-R&#34;,3-R-1,2,3,4,5,6-HEXAHYDRO-2,6-   METHANO-3-BENZAZOCINE   WHEREIN R,R&#39;&#39;,R&#34;, A AND Z ARE AS ABOVE DEFINED, AND IN THE CASE WHERE Z IS CN, CONVERTING THIS GROUP INTO THE CORRESPONDING CO-H GROUP AND IF Y IS HYDROGEN OR -CO-R6, CONVERTING SAID HYDROGEN OR SAID MOIETY INTO A METHYL, CYCLOPROPYLMETHYL OR CYCLOBUTYLMETHYL MOIETY. THE BENZOMORPHANES ARE USEFUL AS ANALGESICS.

United States Patent Oflice" 3,733,330 BENZOMORPHAN DERIVATIVESHans-Werner Schubert and Friedrich Hoilmeister, Wuppertal-Elberfeld,Germany, assignors to Bayer Aktiengesellschaft, Leverkusen, Germany NoDrawing. Filed May 14, 1970, Ser. No. 37,331 Claims priority,application Germany, May 17, 1969, P 19 25 296.1 Int. Cl. C07d 39/00 US.Cl. 260293.54 9 Claims ABSTRACT OF THE DISCLOSURE Benzomorphanes of theformula:

X-C OA-O R wherein R is methyl, cyclopropylmethyl or cyclobutylmethyl; Rand R are the same or different, and are straight or branched chainhydrocarbons of 1 to 5 carbon atoms; X is OH, OR" or wherein R is astraight or branched chain, saturated or unsaturated hydrocarbon of 11to 11 carbon atoms;

R and R are the same or different, and are hydrogen, a straight orbranched chain, saturated hydrocarbon of 1 to 4 carbon atoms, or R and Rtogether with the nitrogen atom form a 5- or -6-membered heterocyclicring which may have oxygen as a second heteroatom; and as a secondheteroatom; and

A is a bivalent, straight or branched chain, saturated or unsaturatedhydrocarbon of 1 to 10 carbon atoms, said hydrocarbon substituted by 1or more phenyl moieties, or said hydrocarbon substituted by 1 or morealkyl, alkoxy, halogen, nitro or acylamino substituted phenyl moieties,and pharmaceutically acceptable non-toxic salts thereof are produced byreacting a benzomorphan of the formula:

wherein R and R" are as above defined, and Y is hydrogen, methyl,cyclopropylmethyl, cyclobutylmethyl, or the moiety -COR wherein R iscyclopropyl or cyclobutyl, in the presence of an acidbinding agent, orby reacting said benzomorphan in the 3,733,330 Patented May 15, 1973form of a metal or ammonium salt with a reactive ester of a hydroxycompound of the formula:

A is as above defined, and Z is C0-X or CN to give a compound of theformula.

wherein R, R, R, A and Z are as above defined, and in the case where Zis ON, converting this group into the corresponding CO--H group and if Yis hydrogen or --COR converting said hydrogen or said moiety into amethyl, cyclopropylmethyl or cyclobutylmethyl moiety.

The benzomorphanes are useful as analgesics.

The present invention is concerned with benzomorphaues and theirproduction. These compounds are useful as analgesics.

It is known that the so-called strongly active or narcotic analgesicsexhibit similar pharmacological effects to that of morphine independentof their chemical composition. As a result, such compounds cause similarconcomitant effects and side-effects as morphine itself and at a highdosage level produce similar toxic phenomena as does morphine. Thus, themorphine-like effect of such compounds which produces morphine-likephysiological and psychic dependents in humans and animals, commonlyknown as morphine addiction, is of great significance.

As a result of these effects, analgesics like morphine and those whichexhibit morphine-like effects are only used under closely supervisedcircumstances in order to minimize the possibility of morphineaddiction. Because of the likelihood of morphine addiction, suchcompounds cannot be used for long term pain relief. Thus, any newanalgesic which exhibits a high activity level and at the same timeeither does not produce a morphine-like addition or dependence, orproduces an addiction or dependence which is less pronounced thanmorphine and the morphine-like analgesics represents a significant andimportant advance in the art.

Clincial-therapeutic experience has demonstrated that the analgesiceffect of known strongly active analgesics is not always suffcient forthe treatment of conditions which produce severe pain, such as the painassociated with carcinoma. In such cases, the analgesic elfectivenesswill outweight the additive side-elfects so that analgesics which arestronger than morphine and morphine-like analgesics would be ofconsiderable and important usage even though such compounds might causeaddiction.

It is well known in the art that both the analegsic effects and theside-effects or concomitant effects of analgesics can be accuratelydetermined in animal experiments. The analgesic effects are particularlyreliably detected in the heat ray test on the tail of a rat, accordingto dAmour and Smith.

The concomitant effects and especially the addiction causing propertiesof analgesics can be determined by testing such compound onmorphine-dependent monkeys, i.e., monkeys addicted to morphine.

Compounds which are tested on morphine-dependent monkeys and whicheither are not capable of replacing morphine or which exert a morphineantagonist effect in such monkeys are considered to be free of morphineaddiction and dependence type properties.

The benzomorphanes of the present invention exhibit a high level ofanalgesic activity and are superior to such known strong anaglesics asmorphine, codeine and pethidine. The benzomorphanes of the presentinvention are superior to these known analgesics either by virtue of astrong analgesic activity, better toleration, or both. In addition, manyof the compounds of the present invention have been shown to be free ofproperties which cause addiction based on recognized animal experiments,or exhibit such properties only to a slight extent. Some of thecompounds of the present invention also have shown usefulness in thetreatment of manic-depressive illness in humans.

The benzomorphanes of the present invention are represented by theformula:

wherein R is methyl, cyclopropylmethyl or cyclobutylmethyl; R' and R"are the same or different, and are a straight or branched chainsaturated hydrocarbon of 1 to carbon atoms, especially alkyl of 1 to 5carbon atoms; X is OH, OR or wherein R' is a straight or branched chain,saturated or unsaturated hydrocarbon of l to 11 carbon atoms, especiallystraight or branched chain alkyl of 1 to 11 carbon atoms or straight orbranched chain alkenyl of 2 to 1-1 carbon atoms;

R and R are the same or different, and are hydrogen, or a straight orbranched chain saturated hydrocarbon of 1 to 4 carbon atoms, especiallyalkyl of 1 to 4 carbon atoms, or R and R together with the nitrogen atomform a 5- or 6-membered heterocyclic ring wherein the nitrogen atom isthe only heteroatom or wherein oxygen is present as a second heteroatom,such as pyrrolidine, piperidine or morpholine; and

A is a bivalent, straight or branched chain, saturated or unsaturatedhydrocarbon of l to 10 carbon atom (i.e. alkylene or alkylidene), abivalent straight or branched chain, saturated or unsaturatedhydrocarbon of 1 to 10 carbon atoms substituted by a member selectedfrom the group consisting of l phenyl group, more than 1 phenyl group,and 1 or more phenyls substituted by alkyl, alkoxy, halogen, nitro oracylamino. In particular, it is preferred that A is alkyl of 1 to 10carbon atoms, alkylene of 1 to 10 carbon atoms, alkenyl of 2 to 10carbon atoms, or said alkyl, said alkylene, or said alkenyl substitutedby phenyl.

These benzomorphanes are produced by reacting a benzomorphan of theformula:

wherein R and R" are as above defined, and Y is hydrogen, methyl,cyclopropylmethyl, cyclobutylmethyl, or a moiety of the formula:

R is cyclopropyl or cyclobutyl, in the presence of an acid-bindingagent, such as potassium carbonate, sodium hydroxide and the like, or byreacting a metal or ammonium salt of compound II with a reactive esterof a hydroxyl compound of the Formula III, for example halides ortosylates,

ZA--OH (III) wherein A is as above defined, and Z is COX or CN wherein Xis as above defined, to give a compound of the Formula IV:

wherein R, R, R", A and Z are above defined, and in the case where Z isCN, converting this group according to methods per se known into thegroup COX and furthermore if Y is hydrogen or the moiety COR convertingY into methyl, cyclopropylmethyl or cyclobutylmethyl by a subsequentreaction according to methods which are per se known to obtain compoundsof the Formula I. The compounds of the Formula I may be converted intopharmaceutically acceptable non-toxic salts by reaction with suitableacids.

The benzomorphanes of the Formula II can be obtained according to theprocess of British 'Pat. No. 1,078,286, according to U.S. Pat. No.3,138,603, or according to J. Med. Chem. 7, 123 (1964).

The reaction above described may be carried out in an aqueous medium orin organic solvents, such as benzene, tetrahydrofurane, acetone,dimetyhlformamide, and the like, at room temperatures or at elevatedtemperatures. Generally, the boiling point of the particular solventselected is chosen.

In the case where Z is COX, the compounds of Formula IV are identical tothe compounds of Formula I. If Z is CN, then the compounds IV must beconverted as above indicated to the compounds of Formula I.

Among the methods for conversion which can be employed include theconversion into esters (X=OR) and carboxylic acids (X=OH) viaimino-ethers, or acid or alkaline hydrolysis, which leads to the primaryacid amides or to carboxylic acids (X=OH).

The carboxylic acid esters (X=R") can be converted by hydrolysis intothe carboxylic acid (X=OH) or by reaction with ammonia primary orsecondary aliphatic amines to the acid amides R4 X=N/ and the acidamides can be converted into carboxylic acids by hydrolysis.

The possible conversions indicated above will be explained by thefollowing scheme of formulae:

The benzomorphanes of the present invention can be administered eitherper se or in the form of their salts, or either the compounds per se ortheir salts may be formulated into pharmaceutical compositions bytechniques per se known by combining the benzomorphan, or the saltthereof, with a pharmaceutically acceptable nontoxic inert diluent orcarrier. Among the preferred salts include the sodium and potassiumsalts in the case of the carboxylic acids, as well as thehydrochlorides, sulphates, phosphates and the like. The liberation ofthe aminoacids, amino-acid-esters and aminoacid-amides' on which thesalts are based, as well as the conversion of these compounds into theirsalts, is a reaction which proceeds according to known procedure. Otherpharmaceutically acceptable non-toxic salts include the alkali salts,the tartrates, citrates, fumarates, maleates, naphthalene-disulphonates,and the like which are known to be useful for human therapy.

Suitable forms for administering the compounds of the present inventionand the pharmaceutical compositions thereof are oral, for exampletablets, dragees, capsules and the like, or by injection by theformation of an injectable solution according to methods which are perse known.

While the amount of the benzomorphanes of the present invention willvary depending upon the severity of the pain, the history of thepatient, and the strength of the particular benzomorphan, i.e. its levelof analgesic activity, the benzomorphanes of the present invention willgenerally be administered in individual dosages of about 1 to mg.,parenterally or enterally. Such dosages may be administered up to fourtimes per day.

Results of pharmacological investigations In Table 1 set forth below,compounds according to the present invention were compared to knownanalgesics which cause addiction such as morphine, codeine andpethidine. In Table 2, the structural formulae of representativecompounds according to the present invention are designated by number.

Turning to Table 1, this table presents a comparison of the analgesicactivity and the compatibility of compounds according to the presentinvention as compared to known addiction causing analgesics, such asmorphine, codeine and pethidine. The toxicity (LD was determined in ratson subcutaneous administration and the analgesic effect was determinedin the heat ray test on the tail of a'rat. The therapeutic index (LD :EDwas calculated from the two values obtained in these investigations.

A test was further carried out as to whether the products of the processcan replace morphine in morphinedependent monkeys or whethermorphine-antagonistic effects are present.

As can be seen from Table 1, compounds 1 and 2 have at least as high atherapeutic index as pethidine. Compound 1 only replaces morphine inmorphine-dependent monkeys in considerably higher doses than morphine,codeine and pethidine, while compound 2 does not replace morphine at allin these animals in tolerated doses.

Compound 3 also does not replace morphine in morphine-dependent monkeysand furthermore exhibits a higher level of analgesic activity and has ahigher therapeutic index than any of the comparison compounds.

Compounds 4, 5, 6, 7, 8, 9 and 10 also only cancel the withdrawalsymptoms of morphine-dependent monkeys at higher doses than thecomparison products. Compounds 8 and 10 exhibit about the same level ofanalgesic activity as morphine. Both substances have a highertherapeutic index than morphine, because of their lower toxicity. Highertherapeutic indices than morphine are also shown by 7 and 9.

Compounds 11, 12, 13, 14, and 16 only cancel the withdrawal symptoms ofmorphine-dependent monkeys in higher doses than the comparisonsubstances, or do not do so at all in tolerated doses. Compounds 12 and14 also exhibit a stronger analgesic activity than morphine.

Compound 17 also exerts a strong analgesic effect and causes withdrawalsymptoms in morphine-dependent monkeys, that is to say the substance isa distinctly active to strongly active morphine-antagonistic agent.

In the case of substances which do not cancel the effect of morphine,previous experience has shown that, a priori, the development of amorphine-like addiction or dependence in man is not to be expected.

Compound 18, because of its low toxicity, has a significantly highertherapeutic index than morphine and the other narcotic analgesicsemployed for comparison.

Compounds 19, 20, 21, 22, 23 and 24, similarly 17, are distinctlystronger active morphine-antagonistic agents. What has been stated for17, therefore, applies to them. Of these compounds, 19, 20, 21, 22 and24 furthermore have a significantly stronger analgesic effect thanmorphine. Because of their low toxicity, compounds 18 to 24 have aconsiderably higher therapeutic index than the comparison products.

Compounds 25, 26 and 27 are not morphine-antagonistic .agents, butcancel the withdrawal symptoms of morphine-dependent monkeys only athigher doses than the comparison products.

Compound 27 exhibits approximately the same level of analgesic activityas morphine, but has a higher therapeutic index than the latter.Compound 26 also has a higher therapeutic index than morphine and theother analgesics employed for comparison.

SUMMARY The compounds according to the present invention described inTable l were compared with morphine, codeine and pethidine in respect ofanalgesic effect, toxicity i.e. toleration and addiction-causingproperties. They are superior to the comparison products in respect ofat least one of these criteria.

TABLE 1 Analgesic Morphine substitution Morphine-antagonistic eifeet,heat Theraeflect on morphine effect on morphine Toxicity, ray test onpeutic dependent monkeys dependent monkeys rat LDro, the tail of aindex, (cancellation of witli- (provocation of withmg.[kg., rat, ED LDW/drawal symptoms), drawal symptoms), Substance s.c mg./kg., s.c. EDmg./kg., s.c. mg./kg., s.c.

- 105 1.52 69 From2 Mmphm" (65-185) (0. 662. 23) Codeine 229 (BS-fig)(3.6-2.2)

2. 2 (1. 7f.$ 114 {{t rortn 1 .fi .t.. p o ,mstgm can 0. 7-2. 9 255{From 6.3,

-0- 8 312 From 12,

From 18 1 ,212 72 From 6,. From 63. -0. 8 312 From (0 2 1 39 Up to s,insignificant -8 31 Up to 6, insignificant 2. 9 Up to 0.3,insignificant. (0.85-8.1) From 1,. From 4, 03: 360 F 0 3 1 rom .194). 33"{From 3, 417 From 1,.

3 125 Do. 8 Up to 0:1, insignificant.

4 -3,s From 0.3;. 44 From 5 323 g t insignificant.

, Up to 0.1 insignificant. (0, 9%} 463 .-{From 0.31

5 From 6, Fwm -2.5 -.....dO., -1. 6 d

1 Distinct or complete cancellation or provocation. 1 Slightcancellation or provocation.

1 3 TABLE 2-Continued N-OH2 l C2H50-CO-(CH2)s-O CH3 C2Ha NCH2

HOOC-CHz-O CH CHa CHa HO O C-(LH-O CH3 CH8 -O Hz i HOOO-CHr-O CH N-C H2-CgHgO-CO-(CHzh-O CH3 N-C Hz H0O C-CHz-O CH3 N-CHrO HOOC-( CH2) r-O CH3EXAMPLE 1 4.6 g. of 2,5,9-trimethyl-2-hydroxy-6,7-benzomorphan aresuspended in 100 ccs. of absolute methanol, mixed with a solution of0.46 g. of sodium in 10 ccs. of absolute methanol and heated for onehour under reflux, while stirring. Thereafter the solvent is removed invacuo. The residue is stirred for A hour with ccs. of absolute benzene,again evaporated to dryness in vacuo, the residue is taken up in ccs. ofdimethylformamide, 4.3 g. of 'ybromobutyric acid ethyl ester are addeddropwise and the mixture stirred for 18 hours at 60. The reactionmixture is concentrated in vacuo and distributed between water andether. After separating off the ether phase, the water phase isextracted twice more with methylene chloride, the combined organicphases are dried by means of sodium sulphate, the solvent is strippedoff in vacuo and the residue is distilled in vacuo, whereupon 4.9 g. of2,5,9- trimethy1-2'-[3-ethoxycarbonylpropoxy-(1)] 6,7 benzomorphan ofboiling point 192-202" are obtained as a viscous oil.

The same compound is obtained if 4.6 g. of2,5,9-trimethyl-2'-hydroxy-6,7-benzomorphan and 3.3 g. of sievedpotassium hydroxide in 100 ccs. of absolute acetone are heated for 12hours under reflux, 4.3 g. of 'y-bromobutyric acid ethyl ester are addeddropwise, the mixture is stirred for a further 12 hours at the boil andfiltered, the filtrate concentrated in vacuo and the residue distilledin vacuo.

EXAMPLE 2 4.9 g. of 5-ethyl-2,9-dimethyl-2-hydroxy-6,7-benzomorphan aredissolved in ccs. of dimethylformamide, mixed With 1.12 g. of powderedpotassium hydroxide, and the mixture stirred for 30 minutes at roomtemperature. A solution of 1.87 g. of chloracetamide in 20 ccs. ofdimethylformamide is then added dropwise over the course of 20 minutesand the whole stirred for 12 hours at 70. The precipitate is filtered01f and the filtrate is concentrated in vacuo, whereupon crystallisationoccurs. The crystalline product is filtered off and recrystallised fromacetone. The 5-ethyl-2,9-dimethyl-2'-carbamoyl-methoxy- 6,7-benzomorphanthus obtained contains half a mol of acetone of crystallization andmelts at 100 to 102. The acetone can be removed by drying at 50 invacuo.

EXAMPLE 3 4.6 g. of 2,S,9-trimethyl-2'-hydroxy-6,7-benzomorphan areconverted into the sodium salt in the manner described under Example 1.100 ccs. of dimethylformamide and 2.6

g. of sodium chloracetate are added and the mixture is warmed slowly to60 whilst stirring. It is stirred for 12 hours at this temperature, thesolvent is removed in vacuo, the residue is taken up in as little wateras possible and the solution adjusted to pH 8 by adding hydrochloricacid. The precipitate which forms is filtered off, washed with water andacetone and dried in vacuo. The 2,5,9-trirnethyl-2'-carboxymethoxy-6,7-benzomorphan decomposes from 205 onwards.

EXAMPLE 4 9.8 g. of 5-ethyl-2,9-dimethyl-2'-hydroxy-6,7-benzomorphan aresuspended in 200 ccs. of absolute methanol, mixed with a solution of0.92 g. of sodium in 20 ccs. of absolute methanol, and stirred for onehour at the boil. The methanol is distilled off in vacuo, 50 ccs. ofabsolute benzene are added, the whole is stirred for A hour at roomtemperature and the solvent is removed in vacuo. The solid residue isdissolved in 120 ccs. of dimethylformamide. After adding 4.6 g. of'y-chlorobutyronitrile, the reaction mixture is warmed for 18 hours to60, whilst stirring, and is concentrated in vacuo, and the residue isdistributed between water and ether. The undissolved constituents arefiltered off. The ether phase is separated off and dried with sodiumsulphate. After removal of the ether, the residue is distilled in vacuoand 5-ethyl-2,9- dimethyl-2'-[3-cyanopropoxy-(l)]-6,7 benzomorphan isobtained as an oil of boiling point 198-204", which crystallises easily.

5-ethyl-2,9-dimethyl-2-cyanomethoxy 6,7 benzomorphan of boiling point190l93 is obtained by analogous procedure from5-ethyl-2,9-dimethyl-2'-hydroxy-6,7-benzomorphan and chloracetonitrile.

EXAMPLE 5 3.9 g. ofZ-cyclobutylmethyl-5,9-dimethyl-2'-[3-ethoxycarbonylpropoxy-(l)]-6,7-benzomorphanare dissolved in a mixture of 20 ccs. of absolute ether and ccs. ofabsolute methanol, mixed with 4.9 ccs. of 2-normal methanolic sodiummethylate solution, shaken, and stirred for 12 hours at room temperatureafter addition of 0.2 cc. of water. The solution is evaporated todryness in vacuo in a rotary evaporator. The residue consists of thesodium salt of 2-cyclobutylmethyl-5,9-dimethyl-2-[3-carboxypropoxy-( l]-6,7-benzomorphan. Colourless powder; decomposition from 225 onwards.

The same compound is obtained if 4.0 g. of2-cyclobutylrnethyl-5.9-dimethyl-2' [3 -ethoxycarbonylpropoxy-1)]-6,7-benzomorphan in 50 ccs. of a mixture of 50 ccs. of dioxane and10 ccs. of water containing 0.4 g. of sodium hydroxide are heated for 4hours under reflux and subsequently evaporated to dryness.

EXAMPLE 6 5.7 g. of5-ethyl-2,9-dimethyl-2'-cyanomethoxy-6,7-benzomorphan are dissolved in30 ccs. of concentrated sulphuric acid and left to stand for 15 hours atroom temperature. The mixture is poured onto ice, rendered alkaline withsodium hydroxide solution whilst cooling and extracted withbenzene-butanol (1:1), the extract is dried by means of sodium sulphate,the solvent is removed in vacuo and the residue is recrystallised fromacetone. The resulting product is identical with the5-ethyl-2,9-dimethyl- 2-carbamoylmethoxy-6,7-benzomorhpan described inExample 2.

EXAMPLE 7 5.7 g. of5-ethyl-2,9-dimethyl-2'-cyanomethoxy-6,7-benzomorphan in 50 ccs. ofconcentrated hydrochloric acid are stirred for 12 hours under reflux.The mixture is subsequently evaporated to dryness, the residue is takenup in water, and a solution of 2.4 g. of sodium hydroxide in water isadded. After evaporation, a solid residue is obtained, which is treatedwith absolute ethanol. The sodium chloride is removed by filtration, thefiltrate is again evaporated to dryness, the residue is triturated withabsolute ethanol, and the product is filtered off and dried in vacuo.The sodium salt of 5-ethyl-2,9-dimethyl 2'carboxymethoxy-6,7-benzomorphan, which is thus obtained, decomposes from193 onwards.

The same compound is obtained if5-ethyl-2,9-dimethyl-2'-carbamoylmethoxy-6,7-benzomorphan is employed inplace of 5-ethyl-2,9-dimethyl-2-cyanomethoxy- 6,7-benzomorphan in thereaction described above.

EXAMPLE 8 A solution of 3.8 g. of2-cyclopropylmethyl-5,9-dimethyl-2'-[ethoxycarbonylpropoxy-(l)] 6,7benzomorphan in 100 ccs. of ethanol is saturated with ammonia and heatedfor several hours to l00 in an autoclave. After evaporation,2-cyclopropylmethyl-5,9- dimethyl-2-[3-carbamoylpropoxy-(l)]6,7-benzomorphan is obtained. Melting point of the hydrochloride,176-179.

EXAMPLE 9 5.0 g. of 2,5,9-trimethyl-2-carboxymethoxy-6,7-benzomorphanare dissolved in ccs. of absolute ethanol and stirred for 3 hours underreflux, while passing in hydrogen chloride. Thereafter the mitxure isevaporated to dryness, the residue is taken up in 100 ccs. of absoluteethanol and the mixture is again heated to the boil for 3 hours whilepassing in hydrogen chloride. After removal of the solvent in vacuo, theresidue is dissolved in a little water, and the solution is renderedalkaline with dilute sodium hydroxide solution whilst cooling and isextracted three times with methylene chloride-ether. The combinedextracts are dried by means of sodium sulphate, concentrated andacidified with a solution of tartaric acid in ether, whereupon thetartrate of 2,5,9-trimethyl-2- ethoxycarbonylmethoxy-6,7-benzomorphanprecipitates. metling point EXAMPLE 10 1.5 g. of hydrogen chloride arepassed into a solution of 5.7 g. of5-ethyl-2,9-dimethyl-2-cyanomethoxy-6,7- benzomorphan in 30 ccs. ofabsolute ethanol, while cooling. The reaction mixture is left to standfor two hours at room temperature and is evaporated to dryness in vacuo.The residue is taken up in water, and the solution is stirred for 10minutes, covered with a layer of ether and rendered alkaline with dilutesodium hydroxide solution while cooling. After separating off the etherphase, the aqueous phase is extracted twice more with ether. Thecombined ether solutions are dried with sodium sulphate, concentrated,and the residue distilled in vacuo. 5-ethyl-2,9-dimethyl 2'ethoxycarbonylmethoxy-6,7- benzomorphan boils at 176180/0.l mm. Hg.

EXAMPLE 1 l 6.5 g. of the sodium salt of 5-ethyl-2,9-dimethyl-2-carboxymethoxy-6,7-benzomorphan are introduced into 100 ccs. of dryethylene chloride, 1.5 g. of hydrogen chloride are then passed in whilestirring and cooling, the mixture is allowed to warm to roomtemperature, 3.6 g. of thionyl chloride are added and the whole isheated under reflux until the evolution of gas has ended and isevaporated to dryness in vacuo. The-residue is taken up in 100 ccs. ofdry ethylene chloride and 3.0 g. of dimethylamine are passed in whilstcooling. After 15 minutes stirring at room temperature, 50 ccs. of 4-normal sodium hydroxide solution are added, and the ethylene chloridephase is separated ofl, dried by means of sodium sulphate and evaporatedto dryness in vacuo. The residue is taken up in acetone and renderedacid with a solution of hydrochloric acid in ether. On further additionof ether, the hydrochloride of5-ethyl-2,9-dimethyl-2-N,N-dimethylcarbamoylmethoxy 6,7 benzomorphanprecipitates. Melting point 206208.

The same compound is obtained if5ethyl-2,9-dimethyl-2-hydroxy-6,7-benzomorphan is reacted withchloracetic acid dimethylamide in the manner described under Example 2.

The following compounds are produced in a manner analogous to thepreceding examples.

2,5,9-trimethyl-2'-(u-ethoxycarbonyl pmethylbenzyloXy)-6,7-benzomorphan, boiling point 04 210 to 212 C2,5,9-trimethyl-2'-(oz-ethoxycarbonyl pchlorobenzyloxy)-6,7-benzomorphan, boiling point M5 215 to 218 C.

2,5,9-trimethyl-2'-(a-ethoxycarbonyl p nitrobenzyloxy)-6,7-benzomorphau,decomposition of the hydrochloride from 167 C. onwards.

2,5,9-trimethyl-2-(a-ethoxycarbonylp-methoxybenzyloxy)-6,7-benzomorphan, decomposition of the hydrochloridefrom 134 C. onwards.

2,'5,9-trimethyl-2-(wethoxycarbonyl pacetamidobenzyloxy)-6,7-benzomorphan, decomposition of the hydrochloridefrom 158 C. onwards.

2,5,9-trimethyl-2'-[3-carboxypropoXy-( 1)] 6,7 benzomorphan, meltingpoint of the sodium salt 144 C.

2,5,9-trimethyl-2'-(a-carboxy p methoxybenzyloxy)- 6,7-benzomorphan,decomposition of the sodium salt from 176 C. onwards.

2,5,9-trimethyl-2-(a-carboxy p-chlorobenzoyloxy)-6,7-

benzomorphan, decomposition of the sodium salt from 205 C. onwards.

5-ethyl-2,9-dimethyl-2-[3-ethoxycarbonylpropoxy 1 6,7-benzomorphan,boiling point M 202 to 206 C.

5-ethyl-2,9-dimethyl-2'- l-ethoxycarbonylpropoxy (l 6,7-benzomorphan,boiling point 03 206 to 212 C.

5-ethyl-2,9-dimethyl-2'-[2-ethoxycarbonylpropoxy (2)]- 6,7-benzomorphan,boiling point '1 180 to 182 C.

-ethyl-2,9-dimethyl-2'-(3-methoxycarbonylprop2-enl-yloxy)-6,7-benzomorphan, boiling point 045 194 to 202 C.

5-ethyl-2,9-dimethyl 2-[10 ethoxycarbonyldecyloxy)-(1)]-6,7-benzomorphan, purified by Craig distribution; oil. Calculated:N 3.06. Found: N 3.00.

5-ethyl-2,9-dimethyl-2-(a ethoxycarbonylbenzyloxy)-6, 7-benzomorphan,decomposition of the hydrochloride from 80 C. onwards.

5-ethyl-2,9-dimethyl-2'-[3 carboxypropoxy (l)]-6,7-

benzomorphan, decomposition of the sodium salt from 208 C. onwards.

5-ethyl-2,9-dimethyl-2'-[1 carboxypropoxy (1)]-6,7-

benzomorphan, decomposition of the sodium salt from 90 C. onwards.

5-ethyl-2,9-dimethyl-2'-[2 carboxypropoxy (2)]-6,7-

benzomorphan, decomposition of the monohydrate of the sodium salt from248 C. onwards.

5-ethyl-2,9-dimethyl-2-(a carboxybenzyloxy)-6,7-benzomorphan,decomposition of the dihydrate of the sodium salt from 216 C. onwards.

5-ethyl-2,9-dimethyl-2'-(3 carboxyprop-2-en-1-yloxy)-6, 7-benzomorphan,decomposition of the monohydrate of the sodium salt from 225 C. onwards.

5-ethy1-2,9 dimethyl-2'-[1 piperidinocarbonylethoxy-(1)]-6,7-benzomorphan, hydrochloride xH O: decomposition from 80 C.onwards.

2 cyclopropylmethyl 5,9dimethyl-2'-isopropoxycarbonylmethoxy-6,7-benzomorphan, boiling point188 to 192 C.

2 cyclopropylmethyl 5,9 dimethyl-2-(undec-lO-en-lyloxycarbonylmethoxy)-6,7-benzomorphan, melting point of the hydrochloride138 to 142 C.

2 cyclopropylmethyl 5,9 dimethyl-2'-[3-ethoxycarbonylpro-poXyU)]-6,7-benzomorphan, boiling point M5 204- to 212 C.

2 cyclopropylmethyl 5,9dimethyl-2'-ethoxycarbonylmethoxy-6,7-benzomorphan boiling point M5 194to 198 C.

2 cyclopropylmethyl 5,9 dimethyl-2-[l-ethoxycarbonylethoxy(1)]-'6,7-benzomorphan, boiling point M9 170 to178 C.

2 cyclopropylmethyl 5,9 dimethy1-2-(a-ethoxycarbon- 18yl-p-nitrobenzyloxy)-6,7-benzomorphan, melting point of thehydrochloride 127 to 129 C. (decomposition).

2 cyclopropylmethyl 5,9dimethyl-2-(a-ethoxycarbonyl-p-chlorobenZyloXy)-'6,7-benzomorphan,boiling point- 0 15 to 226 C.

2 cyclopropylmethyl 5,9dimethyl-2'-(a-ethoxycarbonyl-p-methylbenzyloxy)-6,7-benzomorphan,boiling point 0'1 213 to 218 C.

2 cyclopropylmethyl 5,9dimethyl-2'-(a-ethoxycarbonyl-p-methoxybenzyloxy)-6,7-benzomorphan,boiling point M5 220 to 223 C.

2 cyclopropylmethyl 5,9 dimethyl-2-carboxymethoxy- 6,7-benzomorphan,decomposition of the hemihydrate of the sodium salt from 192 C. onwards.

2 cyclopropylmethyl 5,9dimethyl-2-[1-carboxyethoxy-(l)]-6,7-benzomorphan, decomposition of themonohydrate of the sodium salt from 183 C. onwards.

2 cyclopropylmethyl 5,9 dimet-hyl 2' [3-carboxypropoXy-(l)]-6,7-benzomorphan, decomposition of the sodium salt from C. onwards.

2 cyclopropylmethyl 5,9 dimethyl-2-[3-N,N-dimethylcarbamoylpropoxy-(IH6,7 benzomorphan, boiling point 0 03 to 232 C.

2 cyclopropylmethyl 5 ethyl 9 methyl-2'-[3-ethoxycarbonylpropoxy (1)]6,7 benzomorphan, boiling point 0 25 t0 210 C- 2 cyclopropylmethyl 5ethyl 9 methyl-2'-ethoxycarbonylmethoxy-6,7-benzomorphan, melting pointof the hydrochloride 180 to 182 C.

2 cyclopropylmethyl 5 ethyl 9methyl-2'-o-eth0xycarbonylbenzyloxy-6,7-benzomorphan, boiling point 04225 to 228 C.

2 cyclopropylmethyl 5 ethyl 9 methyl-2-[2-ethoxycarbonylpropoxy (2)] 6,7benzomorphan, boiling point 0,15 '174 to 184 C.

2 cyclopropylmethyl 5 ethyl 9 methyl-2'-[l0-ethoxycarbonyldecyloXy-( 1)]-6,7-benz0morphan, melting point of the hydrochloride 118 to 121 C.

2 cyclopropylmethyl 5 ethyl 9methyl-2-(3-methoxycarbonyl-prop-Z-en-l-yloxy) 6,7-benzomorphan, boilingpoint 02 203 to 210 C.

2 cyclopropylmethyl 5 ethyl 9 methyl-2'-carboxymethoxy-6,7-benzomorphan,decomposition of the sodium salt from 110 C. onwards.

2 cyclopropylmethyl 5 ethyl 9 methyl-2'-[2-carboxypropoxy- (2)]-6,7-benzomorp'han, decomposition of the sodium salt from 75 C.onwards.

2 cyclobutylmethyl 5,9 dimethyl-2-[3-ethoxycarbonylpropoxy-(1)]-6,7-benzomorphan, boiling point 232 to 236 C.

2 cyclobutylmethyl 5,9 dimethyl-2'-ethoxycarbony1-methoxy-6,7-benzomorph'an, boiling point M9 210 to 214 C.

2 cyclobutylmethyl 5,9 dimethyl-2'-carboxymethoxy- 6,7-benzomorphan,decomposition of the monohydrate of the sodium salt from 180 C. onwards.

What is claimed is: 1. A benzornorphan of the formula:

R is methyl, cyclopropylmethyl or cyclobutylmethyl;

R and R" are the same or different, and are methyl or ethyl;

A is straight or branched chain alkylene or alkylidene of 1 to 4 carbonatoms or alkenylene of 2 to 4 carbon atoms, unsubstituted or substitutedby phenyl or phenyl substituted by methyl, methoxy, chloro, nitro oracetylamino;

X is OH, OR, of N/ wherein R is a straight or branched chain alkyl of lto 11 carbon atoms, or straight or branched chain alkenyl of 2 to 11carbon atoms, and R and R are the same or dilferent, and are hydrogen,alkyl of 1 to 4 carbon atoms, or R and R together with the nitrogen atomform a pyrrolidine, piperidine or morpholine ring, or a pharmaceuticallyacceptable non-toxic salt thereof.

2. A compound according to claim 1 wherein R is straight or branchedchain alkyl of 1 to 3 carbon atoms or straight or branched chain alkenylof 2 or 3 carbon atoms, R and R are the same or different, and arehydrogen or alkyl of 1 or 2 carbon atom, or R and R together with thenitrogen atom form a piperidine ring.

3. A compound according to claim 1 wherein R and R are methyl.

4. The compound according to claim 1 which is 5- ethyl 2,9dimethyl-2-[3-ethoxycarbonylpropoxy-(l)]- 6,7-benzomorphan.

5. The compound according to claim 1 which is 2-cyclopropylmethyl-5,9-dimethyl 2' [3-ethoxycarbony1- propoxy- 1)]-6,7-benzomorphan.

6. The compound according to claim 1 which is 2- cyclopropylmethyl 5ethyl 9-methyl-2-[3-ethoxycarbonylpropoxy- 1 ]-6,7-benzomorphan.

7. The compound according to claim 1 which is 2-cyclopropylmethyl-5,9-dimethyl 2' carboxymethoxy-6, 7-benzomorphan.

8. The compound according to claim 1 which is 2- cyclobutylmethyl 5,9dimethyl-2-[3-ethoxycarbony1- propoxy- 1) ]6,7-benzomorphan.

9. The compound according to claim 1 which is 2- cyclobutylmethyl 5,9dimethyl-2'-[3-carboxypropoxy- (1)]-6,7-b enzomorphan.

References Cited UNITED STATES PATENTS 3,322,778 5/1967 Kupchan et a1.260--294.7 3,345,373 10/1967 Gordon et al. 260-294 OTHER REFERENCESMorrison et al. Organic Chemistry, 2nd edition, Allyn and Bacon, Inc.,Boston, Mass. (1966), pp. 562-6.

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl.X.R.

260-240 R, 247.2 A, 247.5 R, Dig. 13; 424267

